PROJECT SUMMARY Host-adapted Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans, is responsible for 21.6 million illnesses annually. A significant percentage of typhoid patients become chronic carriers of S. Typhi and they are a critical reservoir of S. Typhi infection. Persistence of S. Typhi in the tissues is a serious medical problem, especially in areas of the world where comorbidities such as malaria, human immunodeficiency virus, and malnutrition impair the immune system, leading to higher incidences of relapse and acute and recurrent infections. To better combat persistent S. Typhi infection, new insights into the chronic carrier state are needed. Experimental infection of mice with Salmonella enterica serovar Typhimurium (S. Typhimurium) has served as a useful model for the human disease caused by S. Typhi and a murine model of persistent S. Typhimurium infection has been established. We have begun using this model to study fundamental aspects of the chronic carrier state and have published recently that inflammatory monocytes accumulate and persist in tissues of naturally resistant (NRAMP1+) mice infected with S. Typhimurium. These and other subsets of monocytes are an important component of the innate immune response to Salmonella enterica; however, their role in immunity and host defense against infection with Salmonella enterica is just beginning to be worked out. Based on our published findings and unpublished results described in this application, we hypothesize that inflammatory monocytes provide critical protective functions in the host response to persistent S. Typhimurium infection, but that accumulation and persistence of these cells beyond a certain threshold level causes collateral effects that prolong or exacerbate disease. The proposed research will test our hypothesis and elucidate the role of inflammatory monocytes in the pathogenesis of and host response to persistent S. Typhimurium infection. Conceptual advances resulting from the proposed research are expected to provide new insights into the chronic carrier state and thus should have a strong and sustained influence on the field.